RAB25 modulates pit cell commitment by coordinating transforming growth factor-alpha secretion from gastric epithelial cells

EGFR signaling serves as a regulator of lineage commitment in the stomach. A recent study revealed that two different EGFR ligands can induce fate determination of isthmus progenitors in corpus, but the source and regulatory mechanism of the ligands remain unclear. We analyzed single-cell RNA sequencing and found that Rab25 was strongly expressed in epithelial cells in upper corpus glands along with transforming growth factor-alpha (TGFA) associated with pit lineage commitment. Using mouse primary cell culture, we found that Rab25 loss facilitated TGFA secretion and subsequently promoted upregulation of EGFR signaling in the pit region. Long-term alteration of TGFA secretion in Rab25 KO mice caused gastric lesions with massive foveolar hyperplasia. Most importantly, this corpus lesion was ameliorated by neutralization of TGFA. Moreover, RAB25 expression was reduced in human Ménétrier's disease. Collectively, we provide evidence for a physiological role of Rab25 in the gastric environment to maintain normal lineage commitment.